Insulin Resistance Secondary to a High-Fat Diet Stimulates Longitudinal Bone Growth and Growth Plate Chondrogenesis in Mice

Abstract

It is known that overweight children are often more insulin resistant and taller than normal-weight peers. Because it has been hypothesized that insulin is implicated in the obesity-associated growth acceleration, we aimed to determine whether insulin resistance and secondary hyperinsulinemia are the causative mechanisms of such growth acceleration. Three-week-old mice were fed with standard chow or with a high-fat diet without or with daily administration of pioglitazone. After 6 wk, high-fat mice' body and tibial growth, tibial growth plate height, and serum insulin were all greater than those of standard chow-fed mice. High-fat + pioglitazone mice were shorter, their tibial growth and the growth plate height reduced, and their insulin lower than those of high-fat mice. The addition of insulin to the culture medium of mouse metatarsal bones induced the metatarsal linear growth and increased the metatarsal growth plate height. In addition, insulin stimulated cultured chondrocyte proliferation and differentiation, with both effects being prevented by transfection with a small interfering RNA targeted to the insulin receptor. In conclusion, in high fat-fed mice, insulin resistance is causally related to accelerated skeletal growth. Our in vitro findings suggest that insulin may directly modulate skeletal growth by activating the insulin receptor directly at the growth plate.